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P Olyanhydride Degradation and Erosion A Advanced Drug Delivery Reviews 54 (2002) 911–931 www.elsevier.com/locate/drugdeliv P olyanhydride degradation and erosion A. Gopferich¨ * , J. Tessmar Faculty of Pharmacy and Chemistry, Pharmaceutical Technology Unit, University of Regensburg, Universitatsstrasse¨ 31, D-93053 Regensburg, Germany Received 17 March 2002; accepted 19 June 2002 Abstract It was the intention of this paper to give a survey on the degradation and erosion of polyanhydrides. Due to the multitude of polymers that have been synthesized in this class of material in recent years, it was not possible to discuss all polyanhydrides that have gained in significance based on their application. It was rather the intention to provide a broad picture on polyanhydride degradation and erosion based on the knowledge that we have from those polymers that have been intensively investigated. To reach this goal this review contains several sections. First, the foundation for an understanding of the nomenclature are laid by defining degradation and erosion which was deemed necessary because many different definitions exist in the current literature. Next, the properties of major classes of anhydrides are reviewed and the impact of geometry on degradation and erosion is discussed. A complicated issue is the control of drug release from degradable polymers. Therefore, the aspect of erosion-controlled release and drug stability inside polyanhydrides are discussed. Towards the end of the paper models are briefly reviewed that describe the erosion of polyanhydrides. Empirical models as well as Monte-Carlo-based approaches are described. Finally it is outlined how theoretical models can help to answer the question why polyanhydrides are surface eroding. A look at the microstructure and the results from these models lead to the conclusion that polyanhydrides are surface eroding due to their fast degradation. However they switch to bulk erosion once the device dimensions drop below a critical limit. 2002 Elsevier Science B.V. All rights reserved. Keywords: Bioerosion; Polyanhydride; Polymer degradation; Polymer erosion; Modeling Contents 1 . Introduction ............................................................................................................................................................................ 912 2 . Polymer degradation and erosion.............................................................................................................................................. 913 2 .1. Surface erosion versus bulk erosion................................................................................................................................... 913 2 .2. Physicochemical characterization of polyanhydride degradation and erosion......................................................................... 914 3 . Parameters affecting polyanhydride degradation and erosion ...................................................................................................... 915 3 .1. The impact of polymer composition on degradation and erosion .......................................................................................... 915 3 .1.1. Aliphatic polyanhydrides ........................................................................................................................................ 915 3 .1.2. Aromatic polyanhydrides ........................................................................................................................................ 916 *Corresponding author. Tel.: 149-941-943-4843; fax: 149-941-943-4807. E-mail address: [email protected] (A. Gopferich).¨ 0169-409X/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0169-409X(02)00051-0 912 A. Gopferich¨ , J. Tessmar / Advanced Drug Delivery Reviews 54 (2002) 911–931 3 .1.3. Polyanhydride copolymers derived from aromatic and aliphatic monomers................................................................. 917 3 .1.4. Polyanhydrides derived from fatty acids................................................................................................................... 921 3 .1.5. Cross-linked polyanhydrides ................................................................................................................................... 923 3 .2. The impact of geometry on degradation and erosion ........................................................................................................... 923 3 .2.1. Macroscopic matrices ............................................................................................................................................. 923 3 .2.2. Microparticles........................................................................................................................................................ 924 4 . Erosion-controlled drug release from polyanhydrides ................................................................................................................. 924 5 . Polyanhydride erosion modeling............................................................................................................................................... 925 5 .1. Empirical models ............................................................................................................................................................. 925 5 .2. Monte Carlo-based models ............................................................................................................................................... 925 6 . Why polyanhydrides undergo surface erosion............................................................................................................................ 926 7 . Summary and outlook.............................................................................................................................................................. 927 References .................................................................................................................................................................................. 928 1 . Introduction control degradation and, most importantly, they are approved as biocompatible which is a tremendous Degradable polymers have attracted significant advantage over new degradable polymers that have attention for use in numerous medical and biomedi- to undergo time- and cost-intensive biocompatibility cal applications that require the presence of a testing. There have been only a few cases in recent material only for a limited period of time [1]. years, in which new degradable polymers were Especially after implantation into the body, it is custom made for application in humans: poly- highly desirable that the material ‘disappears’ to anhydrides are one of these (Fig. 1). obviate the need for any post-application removal. Polyanhydrides were made with the intention to Many current concepts in the pharmaceutical and have a material at hand that fits to a paradigm as old biotechnological field depend significantly on this as biodegradable materials themselves: the material strategy [2,3]. A good example is parenteral drug should degrade within the time frame of their delivery, by which a dose of drug is typically application. For degradables used in controlled re- intended to be released over an extended period of lease applications this means that the completeness time [4]. Biodegradable polymers can help signifi- of polymer erosion coincides with the end of drug cantly to overcome numerous problems inherent to release. This is hard to achieve with polymers that this concept. The polymers can stabilize the drug degrade over weeks such as PLA and PLGA when reservoir from premature inactivation; concomitant- the drug is intended to be released for only a few ly, the polymer can control the release of drug out of days. Therefore in the early 1980s polyanhydrides the reservoir and finally the degradability of the were discovered for drug delivery applications [6]. material helps to overcome the need for any post- The advantage of polyanhydrides is that they are application removal. made of the most reactive functional group available Based on the outlined advantage of degradable for degradation on the base of passive hydrolysis. polymers there have been numerous polymers ex- How this translates to an enhanced degradation and plored for their suitability to degrade in a biological in a further step to an accelerated drug release was environment. Since the 1970s a plethora of materials subject to a careful characterization of poly- has been synthesized. Moreover, strategies are under anhydrides in the following decades. way to provide polymers on the basis of com- binatorial approaches [5]. Surprisingly, the class of hydrophobic biodegradable polymers has been domi- nated by poly(a-hydroxy acids) such as poly(lactic acid) (PLA) and poly(lactic-co-glycolic acid) (PLGA) for more than 30 years. These materials are available in different compositions that allow to Fig. 1. General polyanhydride structure. A. Gopferich¨ , J. Tessmar / Advanced Drug Delivery Reviews 54 (2002) 911–931 913 It is the intention of this review to shed some light achieve with our experiments is to find at least a on polyanhydride degradation and erosion in vitro to crude forecast of the in vivo degradation behavior. elucidate the consequences that result from their That this is not a trivial task is documented by degradation and erosion behavior. First, both pro- numerous publications on this issue in the current cesses will be defined and
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